Diorganotin(IV) Derivatives of Substituted Benzohydroxamic Acids with High Antitumor Activity

Abstract

A series of diorganotin(IV) and dichlorotin(IV) derivatives of 4-X-benzohydroxamic acids, [HL₁ (X = Cl) or HL₂ (X = OCH₃)] formulated as [R₂SnL₂] (R = Me, Et, nBu, Ph or Cl; L = L₁ or L₂), along with their corresponding mixed-ligand complexes [R₂Sn(L₁)(L₂)] have been prepared and characterized by FT-IR, ¹H, ¹³C, and ¹¹⁹Sn NMR spectroscopy, mass spectrometry, elemental analysis, and melting points. In addition, single-crystal X-ray diffraction analyses were carried out for [Me₂SnL₂] (L = L₁ or L₂), which show coordination structures intermediate between distorted octahedra and bicapped tetrahedra. The hydroxamate ligands are asymmetrically coordinated by the oxygen atoms, the carbonyl oxygen atom is further away from the metal center than the other oxygen atom. The complexes are stable monomeric species; most of them are soluble not only in chlorohydrocarbon solvents, but also in alcohols and hydroalcoholic solutions. In polar solvents, the mixed-ligand complexes gradually decompose into the corresponding single-ligand complex couples. The complexes exhibit in vitro antitumor activities (against a series of human tumor cell lines) which, in some cases, are identical to, or even higher than, that of cisplatin. For the dialkyltin complexes, the activity increases with the length of the carbon chain of the alkyl ligand and is higher in the case of the chloro-substituted benzohydroxamato ligand. The [nBu₂Sn(L₁)₂] complex displays a high in vivo activity against H22 liver and BGC-823 gastric tumors, and has a relatively low toxicity.